Most people who have heard of ketamine know it is a recreational drug, a substance whose dissociative qualities have made it popular in the club scene since the nineteen-eighties. What many do not know is that ketamine is currently at the cutting edge of research into treatment-resistant depression.
“There have now been multiple research trials that confirm and validate the rapid and efficacious actions of ketamine for the treatment of depression,” wrote Ronald S. Duman, a former professor of psychiatry and neuroscience at Yale University School of Medicine, in a 2018 article for the scientific journal Cerebrum, before adding that there were “still some reservations” about how the drug achieves its effects.
What is ketamine?
In chemical terms, ketamine is anarylcyclohexamine, a class of compounds that have long been of interest to scientists for their dissociative, hallucinogenic, and euphoriant effects. Like other arylcyclohexamines such as phencyclidine (PCP), ketamine was first synthesized by pharmaceutical researchers trying to create new anesthetic drugs.
Ketamine’s dissociative qualities made it an effective pain-management tool, and the fact that it didn’t impede the respiratory system meant that medics on the front lines without access to ventilators could still use it safely on wounded soldiers requiring emergency surgery. When the Vietnam War broke out, it was quickly adopted as a battlefield anesthetic.
As a dissociative, it causes people who take it to feel outside of their environment — anxieties melt away, and users feel like they are observing the world differently. And as researchers began to notice in the late nineteen-nineties, some users find that ketamine also has a pronounced antidepressant effect that lasts far longer than the initial high.
The answer to the question “how long does it stay in your system?” is pretty exact: ketamine has a half-life of about forty-five minutes, so within twenty-four hours of taking the drug, most of it will be out of the patient’s system. But this is not the same as asking “how long does ketamine last?”
The intense high of the “K hole” is relatively short, feelings of warmth and happiness can linger for hours, but the antidepressant effects seem to be much longer — in some cases, a single dose of ketamine can cause treatment-resistant depression to go into remission for weeks. This is one of the reasons researchers have become so interested in understanding what it does to the brain.
As Jamie Sleigh, a professor of anesthesiology at the University of Auckland put it in an article for Trends in Anesthesia and Critical Care, “Ketamine’s effects in chronic pain, and as an antidepressant, far outlast the actual drug levels, and are probably mediated by a secondary increase in structural synaptic connectivity.”
What does ketamine do?
One of the strange things about ketamine is the fact that while researchers have a general answer to the question “what does it do?” they are still trying to figure out the why and the how.
Most antidepressant medications work by increasing levels of serotonin through the use of selective serotonin reuptake inhibitors (SSRIs). Serotonin is a neurotransmitter that helps relay messages between nerve endings in the brain, and lack of serotonin can lead to decreased levels of happiness and well-being. While it improves mood and has antidepressant effects, it doesn’t do so by boosting serotonin.
“It’s not entirely clear how ketamine works,” Dr. Robert C. Meisner, the medical director of ketamine service at McLean Hospital’s psychiatric neurotherapeutics program, explains in a post for the Harvard Health Blog. “Because it exerts an antidepressant effect through a new mechanism, ketamine may be able to help people successfully manage depression when other treatments have not worked.”
Meisner believes it has something to do with how ketamine impacts the neurotransmitter glutamate. It binds to NMDA receptors in the brain, activating AMPA receptors that enable neurons to communicate with each other through different pathways, affecting mood and cognition. It may also reduce inflammation linked to various mood disorders.
“Most likely,” he concludes, “it works in several ways at the same time, many of which are being studied.”
How does ketamine therapy work?
It remains a controlled substance in many countries, but as the scientific evidence for ketamine’s effectiveness as an antidepressant has grown, research centers and specialized clinics like Ketamine Health Centers have started offering ketamine therapy on an experimental basis.
There are two forms of ketamine therapy currently available in the United States. The first involves a ketamine infusion, in which racetic ketamine is administered intravenously. Because ketamine infusion can lead to increased blood pressure and nausea, this is usually done at a clinic licensed to offer this form of treatment so patients can be monitored for adverse reactions.
The second form of ketamine therapy is via an esketamine nasal spray, which is easier to administer, more widely available, and may have less of an impact on blood pressure.
Many patients who have suffered from treatment-resistant depression for years claim that ketamine therapy has completely changed their lives, and the popularity of ketamine therapy has led to growing media interest, as high-profile articles in outlets like The New York Times and The Guardian.
But while physicians like Meisner are optimistic about the current research, some medical bodies have sounded a note of caution, arguing that care should be taken until we have a clearer answer to the question “what does ketamine do?”
A 2017 statement issued by the Royal College of Psychiatrists noted there are still a lot of details to be ironed out. “Despite clinical trials showing rapid improvement in mood after ketamine infusion, there are still significant gaps in our knowledge about dosage levels, treatment protocols and the effectiveness and safety of long-term use.”
At this point, the latest research into ketamine indicates it has remarkable potential as an antidepressant. But understanding why that is, and how it can best be put to widespread therapeutic use, is the question that will need to be answered before it can become a mainstream option for treating depression and bipolar disorder.